Structure-based design of 2,4-diaminopyrimidine derivatives bearing pyrrolyl group as ALK & ROS1 inhibitors
Structure-based design of 2,4-diaminopyrimidine derivatives bearing pyrrolyl group as ALK & ROS1 inhibitors
复制标题
基于结构的 ALK 吡咯基 2,4-二氨基嘧啶衍生物的设计
DOI：
10.1039/c9nj05980f
复制
发表时间：
2020
影响因子：
3.3
通讯作者：
Xin Zhai
中科院分区：
文献类型：
--
作者：
Jie Wang;Shangfei Wei;Tong Li;Lingyun Xing;Meng Cao;Nan Jiang;Ming Guo;Daiying Zuo;Xin Zhai
为了开发有效的ALK和ROS1双抑制剂，以塞瑞替尼与ALKwt蛋白共晶结构为基础，设计合成了28个含有吡啶基的2,4-二氨基嘧啶衍生物（9a-9n和10a-10n）。大多数化合物对ALK和ROS1成瘾细胞表现出相当大的活性；化合物10d对Karpas299、H2228和HCC78具有较好的活性，IC50值分别为0.01、0.08和0.042 μM。随后，我们选择了7个化合物进行体外激酶研究，结果发现10d对ALK、ALKL1196M和ROS1的IC50值分别为1.8、4.3和3.6 nM。此外，生物实验显示化合物10d诱导细胞凋亡呈剂量依赖性。最终，分子对接研究提出了与ALKwt和ROS1之间合理且最佳的结合作用。
In order to develop potent ALK and ROS1 dual inhibitors, twenty-eight 2,4-diaminopyrimidine derivatives (9a–9n and 10a–10n) bearing a pyrrolyl moiety were designed and synthesized based on the co-crystal structure of ceritinib with ALKwt protein. Most compounds displayed considerable activity against ALK and ROS1 addicted cells; meanwhile, compound 10d showed excellent activity against Karpas299, H2228 and HCC78 with IC50 values of 0.01, 0.08 and 0.042 μM. Subsequently, seven compounds were selected for kinase studies in vitro, resulting in the discovery of 10d with IC50 values of 1.8, 4.3 and 3.6 nM against ALK, ALKL1196M and ROS1, respectively. Furthermore, the biological assays revealed that compound 10d induced cell apoptosis in a dose-dependent manner. Ultimately, molecular docking studies presented reasonable and optimal binding interactions with ALKwt and ROS1.